Our overall research goal is to optimize aerobic exercise training as therapy for patients with pulmonary arterial hypertension (PAH) by investigating safety, efficacy, and mechanisms of exercise responses to complementary training approaches. We hypothesize that improved functional outcomes for PAH require training parameters that allow for maximal skeletal and cardiac muscle mitochondrial adaptations without inducing greater pulmonary artery pressures, right wall stress, and accelerated right ventricular (RV) maladaptive hypertrophy and dysfunction. Though traditionally discouraged for PAH, data now suggests that exercise might not only be safe, but may actually favorably impact morbidity and mortality. Controversies exist regarding the stage of disease for which this intervention may be beneficial, and the incertitude of how training workload impacts pulmonary vascular hemodynamics and potentially life-threatening RV hypertrophy requires further investigation. The use of a training program optimally-tailored relative to individual aerobic capacity (% of measured VO2max) has not been investigated for PAH, which hinders the translation of this potential therapeutic to optimal clinical practice. Therefore, our objective isto evaluate exercise at prescribed relative intensity as therapy in PAH, in terms of underlying mechanisms for protective effects, and optimization of training protocols to minimize risk and maximize outcomes. Aim 1 will evaluate how the parameter of intensity impacts acute exercise responses over the course of disease development. Aim 2 will evaluate how the training protocol may be manipulated to maximize functional gain via enhanced skeletal muscle metabolic adaptations without promoting higher exercise pulmonary pressures and accelerated RV hypertrophy. There are two major strengths of the proposed project. The first is our novel assessment of hemodynamics during exercise in PAH rats using implantable telemetry to permit the study of pulmonary pressures relative to exercise intensity and disease stage. The second is our assessment of maximal aerobic capacity via metabolic treadmill testing which serves as both a valuable functional endpoint translatable to humans and also permits exercise intensity to be set relative to each animal's capability. This is essential for the translation of dose-response observations in the rat model to, ultimately, optimized exercise training prescription for patients with PAH.